News Topics: SUDEP

Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk [Study Featuring the Work of CURE Grantee, Kenneth Myers]

Significance: These findings suggest that autonomic dysfunction is associated with Sudden Unexpected Death in Epilepsy (SUDEP) risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

Objective: SUDEP is a tragic and devastating event for which the underlying pathophysiology remains poorly understood; this study investigated whether abnormalities in heart rate variability (HRV) are linked to SUDEP in patients with epilepsy due to mutations in sodium channel (SCN) genes.

Methods: We retrospectively evaluated HRV in epilepsy patients using electroencephalographic studies to study the potential contribution of autonomic dysregulation to SUDEP risk. We extracted HRV data, in wakefulness and sleep from 80 patients with drug?resistant epilepsy, including 40 patients with mutations in SCN genes and 40 control patients with non?SCN drug?resistant epilepsy. From the SCN group, 10 patients had died of SUDEP. We compared HRV between SUDEP and non?SUDEP groups, specifically studying awake HRV and sleep:awake HRV ratios.

Results: The SUDEP patients had the most severe autonomic dysregulation, showing lower awake HRV and either extremely high or extremely low ratios of sleep?to?awake HRV in a subgroup analysis. A secondary analysis comparing the SCN and non?SCN groups indicated that autonomic dysfunction was slightly worse in the SCN epilepsy group.

Wearable Devices for Sudden Unexpected Death in Epilepsy Prevention

Sudden unexpected death in epilepsy (SUDEP) is most often associated with the occurrence of generalized tonic-clonic seizures (GTCS), a seizure type that can now be detected with high sensitivity and specificity by wearable or bed devices. The recent development in such devices and their performance offer multiple opportunities to tackle SUDEP and its prevention. Reliable GTCS detection might help physicians optimize antiepileptic treatment, which could in turn reduce the risk of SUDEP. GTCS?triggered alarms can lead to immediate intervention by caregivers that are also likely to decrease the odd of SUDEP.

The biosignals used to detect GTCS might provide novel SUDEP biomarkers, in particular, by informing on several important characteristics of the ictal and postictal periods (type of GTCS duration of tonic phase, rotation in the prone position, presence and duration of postictal immobility and bradycardia, rise in electrodermal activity). Other biosensors not yet used for detecting GTCS might provide complementary information, such as the presence and intensity of ictal/postictal hypoxemia.

The above biomarkers, if strongly predictive, could help identify patients at very high risk of SUDEP, enabling better assessment of individual risk, as well as selection of appropriate patients for clinical studies aiming at preventing SUDEP. The same biosignals could also be used as ancillary biomarkers to test the impact of various interventions before moving to highly challenging randomized controlled trials with SUDEP as a primary outcome.

Findings on Bradycardia Detailed by Investigators at Veterans Affairs Medical Center (Severe Peri-Ictal Respiratory Dysfunction is Common in Dravet Syndrome)

Bradycardia are discussed in a new report. According to news reporting out of Iowa City, Iowa, by NewsRx editors, research stated, “Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms.”

A quote from the research from Veterans Affairs Medical Center: “Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1a(R1407x/+) loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death.”

According to the news editors, the research concluded: “SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.”

CURE Discovery: Potential Target Area in the Brain for Prevention of Epilepsy-Related Sudden Death

An area of the brain known as the amygdala may be critical in the conscious control of breathing, making it an important target area for research into epilepsy-related sudden death, according to a study recently published by CURE Grantee Dr. William Nobis of Northwestern University Feinberg School of Medicine.1 As part of a team led by Dr. Christina Zelano, also of Northwestern University, Dr. Nobis found that stimulation of the amygdala consistently induced apnea, or disrupted breathing, in a group of individuals with temporal lobe epilepsy. This finding is significant because it points to a possible role of the amygdala in what may be the most severe epilepsy-related complication, Sudden Unexpected Death in Epilepsy (SUDEP).

SUDEP occurs when a seemingly healthy person with epilepsy dies for no obvious reason,2 most often at night or during sleep. While research suggests that several factors including respiratory and cardiac dysfunction contribute to SUDEP,3,4 the precise biological processes remain unknown. By implanting electrodes into the brains of seven patients undergoing surgical evaluation for temporal lobe epilepsy, Dr. Nobis and his team were able to pinpoint specific regions of the amygdala that are important in controlling respiration, identifying areas possibly important in the cessation of respiration that characterizes SUDEP. Furthermore, the team found that by instructing patients to inhale during an apnea-inducing stimulation of the amygdala, they were able to prevent apnea providing an area upon which to focus development of therapeutic strategies to prevent SUDEP.

With funding from CURE, Dr. Nobis is now pushing this research to uncover the mechanisms behind SUDEP even further. He and his team think that the amygdala may be activated during seizures, causing it to lead to cessation of respiration and SUDEP. By using a genetic animal model of epilepsy that has a high rate of SUDEP, the team hopes to identify and examine the specific neurons within the amygdala that project to important respiratory centers in other parts of the brain, allowing the amygdala to influence respiratory function – and the loss of respiratory function that occurs in SUDEP.

Early results from Dr. Nobis’s current CURE project have begun to identify populations of neurons in the amygdala that project to areas of the brain important in respiration. The team next plans on examining how these neurons are activated in response to seizures, and how changes in the excitability of these neurons might correspond with changes in respiratory function that could lead to SUDEP.

In the future, Dr. Nobis hopes to be able to determine whether it is possible to target this subset of neurons within the amygdala to prevent SUDEP from occurring, providing a large step forward for SUDEP research and possible therapies for SUDEP prevention. Thanks to CURE-funded researchers like Dr. Nobis, we are moving closer to being able to eliminate the sudden and devastating death of individuals with epilepsy.

1 Nobis WP et al. Amygdala-stimulation-induced apnea is attention and nasal-breathing dependent. Ann Neurol 2018; 83(3):460-471.
2 Nashef. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997; 38(11 Suppl):S6-8.
3 Surges et al. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat Rev Neurol 2009; 5(9):492-504.
4 Bagnall et al. Genetic basis of sudden unexpected death in epilepsy. Front Neurol 2017; 8:348.

Study: Resolving Ambiguities in SUDEP Classification

Objective: To examine the consistency of applying the Nashef et al (2012) criteria to classify sudden unexpected death in epilepsy (SUDEP).

Methods: We reviewed cases from the North American SUDEP Registry (n = 250) and Medical Examiner Offices (n = 1301: 698 Maryland, 457 New York City, 146 San Diego). Two epileptologists with expertise in SUDEP and epilepsy?related mortality independently reviewed medical records, scene investigation, autopsy, and toxicology and assigned a SUDEP class.

Results: Major areas of disagreement arose between adjudicators concerned differentiating (1) Definite SUDEP Plus Comorbidity from Possible SUDEP and (2) Resuscitated (Near) SUDEP from SUDEP. In many cases, distinguishing between contributing and competing causes of death when trying to classify Definite SUDEP Plus Comorbidity versus Possible SUDEP is ambiguous and relies on judgement. Similarly, determining if an intervention was lifesaving or not (Resuscitated SUDEP or Not SUDEP), or if resuscitation merely delayed SUDEP (Resuscitated SUDEP or SUDEP) is often a judgement call and can differ between experienced adjudicators. Given these persisting ambiguities, we propose more explicit criteria for distinguishing these categories.

Significance: Accurate and consistent classification of cause of death among individuals with epilepsy remains a dire public health concern. SUDEP is likely underestimated in national health statistics. Greater standardization of criteria among epilepsy researchers, medical examiners, and epidemiologists to determine cause and classify death will lead to more accurate tracking of SUDEP and other epilepsy?related mortalities.

Study: Decreasing the Risk of SUDEP – Structured Communication of Risk Factors for Premature Mortality in People with Epilepsy

Conclusion: Structured discussion results in behavioural change which reduces individual risk factors. This impact seems higher in those who are at higher risk currently. It is important clinicians share risk information with individuals as a matter of public health and health promotion.

Background: Good practice guidelines highlight the importance of making people with epilepsy aware of the risk of premature mortality in epilepsy particularly due to Sudden Unexpected Death in Epilepsy (SUDEP). The SUDEP and Seizure Safety Checklist (“Checklist”) is a structured risk communication tool used in UK clinics. It is not known if sharing structured information on risk factors allows individuals to reduce SUDEP and premature mortality risks.

Aim: To ascertain if the introduction of the Checklist in epilepsy clinics lead to individual risk reduction.

Method: The Checklist was administered to 130 consecutive people with epilepsy attending an epilepsy specialised neurology clinic and 129 attending an Intellectual Disability epilepsy clinic within a 4 month period. At baseline, no attendees at the neurology clinic had received formal risk advice while all attending the ID clinic had on multiple occasions for six years. A year later the Checklist was re?administered to each group and scores were compared with baseline and between groups.

Results: Of 12 risk factors considered there was an overall reduction in mean risk score for the general population (p=0.0049) but not for the ID population (p=0.322). Sub analysis of 25% at most risk of both populations showed both sets had a significant reduction in risk scores (p<0.001).

Study: Cardiac Arrhythmia and Neuroexcitability Gene Variants in Resected Brain Tissue from Patients with Sudden Unexpected Death in Epilepsy (SUDEP)

[Researcher’s] data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.

Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown, but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction.

Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including ARRB2, ITPR1, GABRR2, SSTR5, GRIK1, CTNAP2, GRM8, GNAI2 and GRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including KCNMB1, KCNIP1, DPP6, JUP, F2, and TUBA3D, which were not present in living epilepsy controls.

Study: Cardiac Arrhythmia and Neuroexcitability Gene Variants in Resected Brain Tissue from Patients with Sudden Unexpected Death in Epilepsy (SUDEP)

[Researcher’s] data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.

Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown, but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction.

Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including ARRB2, ITPR1, GABRR2, SSTR5, GRIK1, CTNAP2, GRM8, GNAI2 and GRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including KCNMB1, KCNIP1, DPP6, JUP, F2, and TUBA3D, which were not present in living epilepsy controls.

Prof. Ley Sander Discusses Preventing SUDEP and How to Build Research Around SUDEP: Video from CURE Frontiers in Research Seminar Series

Video is available from the CURE Frontiers in Research Seminar Series talk given by Professor Ley Sander, discussing SUDEP prevention and research.

Talk summary: Individuals with epilepsy, particularly those with uncontrolled epilepsy, are at a much greater risk of premature death than those without. In fact, the standardized mortality ratio in those with epilepsy is between 2 and 3. In the UK, the most common cause of epilepsy-related death is due to Sudden Unexpected Death in Epilepsy (SUDEP), which accounts for up to one-fifth of deaths in some series. SUDEP is more common in those with frequent convulsive seizures (particularly nocturnal seizures) and in those with drug-resistant epilepsy. While the causes of SUDEP are unknown, the most commonly suggested underlying mechanisms are cardiac arrhythmias, respiratory depression and “cerebral shutdown.” Because no preventative measures currently exist, an understanding of SUDEP risk factors, potential mechanisms and the effectiveness of preventative measures is essential. To this end, there are a multitude of opportunities available in the field of SUDEP research and these opportunities will be interactively discussed during the presentation.

National Association of Medical Examiners position paper: Recommendations for the investigation and certification of deaths in people with epilepsy

Sudden unexpected death of an individual with epilepsy can pose a challenge to death investigators, as most deaths are unwitnessed, and the individual is commonly found dead in bed. Anatomic findings (eg, tongue/lip bite) are commonly absent and of varying specificity, thereby limiting the evidence to implicate epilepsy as a cause of or contributor to death. Thus it is likely that death certificates significantly underrepresent the true number of deaths in which epilepsy was a factor.

To address this, members of the National Association of Medical Examiners, North American SUDEP Registry, Epilepsy Foundation SUDEP Institute, American Epilepsy Society, and the Centers for Disease Control and Prevention constituted an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of autopsy and toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance of epilepsy-related deaths.

The recommendations provided in this paper are intended to assist medical examiners, coroners, and death investigators when a sudden unexpected death in a person with epilepsy is encountered.